Dataset Information

Deletion of hippocampal Glucocorticoid receptors unveils sex-biased microRNA expression and neuronal morphology alterations in mice.

ABSTRACT: Sex differences in the brain have prompted many researchers to investigate the underlying molecular actors, such as the glucocorticoid receptor (GR). This nuclear receptor controls gene expression, including microRNAs (miRNAs), in non-neuronal cells. Here, we investigated sex-biased effects of GR on hippocampal miRNA expression and neuronal morphology by generating a neuron-specific GR knockout mouse (Emx1-Nr3c1 ^-/-). The levels of 578 mature miRNAs were assessed using NanoString technology and, in contrast to males, female Emx1-Nr3c1 ^-/- mice showed a substantially higher number of differentially expressed miRNAs, confirming a sex-biased effect of GR ablation. Based on bioinformatic analyses we identified several transcription factors potentially involved in miRNA regulation. Functional enrichment analyses of the miRNA-mRNA interactions revealed pathways related to neuronal arborization and both spine morphology and density in both sexes. Two recognized regulators of dendritic morphology, CAMKII-α and GSK-3β, increased their protein levels by GR ablation in female mice hippocampus, without changes in males. Additionally, sex-specific effects of GR deletion were observed on CA1 neuronal arborization and dendritic spine features. For instance, a reduced density of mushroom spines in apical dendrites was evidenced only in females, while a decreased length in basal dendrites was noted only in males. However, length and arborization of apical dendrites were reduced by GR ablation irrespective of the sex. Overall, our study provides new insights into the sex-biased GR actions, especially in terms of miRNAs expression and neuronal morphology in the hippocampus.

SUBMITTER: Tejos-Bravo M

PROVIDER: S-EPMC7906897 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Deletion of hippocampal Glucocorticoid receptors unveils sex-biased microRNA expression and neuronal morphology alterations in mice.

Tejos-Bravo Macarena M Oakley Robert H RH Whirledge Shannon D SD Corrales Wladimir A WA Silva Juan P JP García-Rojo Gonzalo G Toledo Jorge J Sanchez Wendy W Román-Albasini Luciano L Aliaga Esteban E Aguayo Felipe F Aguayo Felipe F Olave Felipe F Maracaja-Coutinho Vinicius V Cidlowski John A JA Fiedler Jenny L JL

Neurobiology of stress 20210209

Sex differences in the brain have prompted many researchers to investigate the underlying molecular actors, such as the glucocorticoid receptor (GR). This nuclear receptor controls gene expression, including microRNAs (miRNAs), in non-neuronal cells. Here, we investigated sex-biased effects of GR on hippocampal miRNA expression and neuronal morphology by generating a neuron-specific GR knockout mouse (<i>Emx1-Nr3c1</i> <sup>-/-</sup>). The levels of 578 mature miRNAs were assessed using NanoStri ...[more]

PMID: 33665240

Similar Datasets

Project description:BackgroundMaternal antenatal corticosteroid treatment is standard care to accelerate fetal maturation. However, there are growing concerns that antenatal corticosteroid administration may harm fetal neurodevelopment. Quantitative assessments of the effects of antenatal corticosteroid on the neonates have not been performed and poorly understood about their complex biology.ResultsWe collected Methylation BeadChips-generated DNA methylation data from the Gene Expression Omnibus (GEO) database and then employed "multi-tissue predictor" to quantify the DNAm age of saliva from 36 preterm neonates, which were stratified by the absence (n = 12) or presence (n = 24) of antenatal corticosteroid exposure, as well as 36 full-term neonates. Next, the DNAm age of human lung fibroblast IMR90 cells and human fetal multipotent hippocampal progenitor HPC cells, with or without glucocorticoid treatment, was also determined. We observed that the DNAm age of full-term neonates was significantly higher than that of the preterm neonates, and antenatal corticosteroid exposure accelerated the DNAm age of preterm neonates, while glucocorticoid exposure accelerated the DNAm age of IMR90 cells. Conversely, dexamethasone exposure delayed the DNAm age of HPC cells during the proliferation phase. It is noteworthy that 65% of the differentially methylated probes (DMPs) linked to the multi-tissue predictor marked CpGs and corticosteroid exposure in IMR90 cells exhibited comparable methylation patterns with the DMPs associated with the antenatal corticosteroid exposure in preterm neonates. Conversely, the majority of these DMPs exhibited inverse methylation alterations in dexamethasone-induced HPC cells. Furthermore, the epigenome-wide association study (EWAS) trait enrichment analyses of the DMPs linked to the antenatal corticosteroid exposure in preterm neonates revealed significant associations with prenatal adverse environmental exposure, growth and development, and neuropsychiatric disorders.ConclusionsOur results identified the cellular and molecular evidences of epigenetic clock changes in neonatal growth and developmental trajectories with the interference of antenatal corticosteroid treatment and provided potential clinical guidance for the future development of noninvasive fetal assessments to identify pregnant women who could benefit from antenatal corticosteroid in a wider gestational age.

Project description:Although glucocorticoids (GCs) are known to exert numerous effects in the hippocampus, their chronic regulatory functions remain poorly understood. Moreover, evidence is inconsistent regarding the long-standing hypothesis that chronic GC exposure promotes brain aging/Alzheimer disease. Here, we adrenalectomized male F344 rats at 15 months of age, maintained them for 3 months with implanted corticosterone (CORT) pellets producing low or intermediate (glucocorticoid receptor-activating) blood levels of CORT, and performed microarray/pathway analyses in hippocampal CA1. We defined the chronic GC-dependent transcriptome as 393 genes that exhibited differential expression between intermediate and low CORT groups. Short-term CORT (4 days) did not recapitulate this transcriptome. Functional processes/pathways overrepresented by chronic CORT-up-regulated genes included learning/plasticity, differentiation, glucose metabolism, and cholesterol biosynthesis, whereas processes overrepresented by CORT-down-regulated genes included inflammatory/immune/glial responses and extracellular structure. These profiles indicate that GCs chronically activate neuronal/metabolic processes while coordinately repressing a glial axis of reactivity/inflammation. We then compared the GC transcriptome with a previously defined hippocampal aging transcriptome, revealing a high proportion of common genes. Although CORT and aging moved expression of some common genes in the same direction, the majority were shifted in opposite directions by CORT and aging (eg, glial inflammatory genes down-regulated by CORT are up-regulated with aging). These results contradict the hypothesis that GCs simply promote brain aging and also suggest that the opposite direction shifts during aging reflect resistance to CORT regulation. Therefore, we propose a new model in which aging-related GC resistance develops in some target pathways, whereas GC overstimulation develops in others, together generating much of the brain aging phenotype.

Project description:Neuronal polarization underlies the ability of neurons to integrate and transmit information. This process begins early in development with axon outgrowth, followed by dendritic growth and subsequent maturation. In between these two steps, the axon initial segment (AIS), a subcellular domain crucial for generating action potentials (APs) and maintaining the morphological and functional polarization, starts to develop. However, the cellular/molecular mechanisms and receptors involved in AIS initial development and maturation are mostly unknown. In this study, we have focused on the role of the type-1 cannabinoid receptor (CB1R), a highly abundant G-protein coupled receptor (GPCR) in the nervous system largely involved in different phases of neuronal development and differentiation. Although CB1R activity modulation has been related to changes in axons or dendrites, its possible role as a modulator of AIS development has not been yet explored. Here we analyzed the potential role of CB1R on neuronal morphology and AIS development using pharmacological and RNA interference approaches in cultured hippocampal neurons. CB1R inhibition, at a very early developmental stage, has no effect on axonal growth, yet CB1R activation can promote it. By contrast, subsequent dendritic growth is impaired by CB1R inhibition, which also reduces ankyrinG density at the AIS. Moreover, our data show a significant correlation between early dendritic growth and ankyrinG density. However, CB1R inhibition in later developmental stages after dendrites are formed only reduces ankyrinG accumulation at the AIS. In conclusion, our data suggest that neuronal CB1R basal activity plays a role in initial development of dendrites and indirectly in AIS proteins accumulation. Based on the lack of CB1R expression at the AIS, we hypothesize that CB1R mediated modulation of dendritic arbor size during early development indirectly determines the accumulation of ankyrinG and AIS development. Further studies will be necessary to determine which CB1R-dependent mechanisms can coordinate these two domains, and what may be the impact of these early developmental changes once neurons mature and are embedded in a functional brain network.

Dataset Information

Deletion of hippocampal Glucocorticoid receptors unveils sex-biased microRNA expression and neuronal morphology alterations in mice.

Publications

Deletion of hippocampal Glucocorticoid receptors unveils sex-biased microRNA expression and neuronal morphology alterations in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets